AXIN1

Axin 1
PDB rendering based on 1dk8.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1DK8​, 1EMU​, 1O9U​, 3ZDI​, 4B7T​, 4NM0​, 4NM3​, 4NM5​, 4NM7​, 4NU1​
Identifiers
Symbols	AXIN1 ; AXIN; PPP1R49
External IDs	OMIM: 603816 MGI: 1096327 HomoloGene: 2614 ChEMBL: 1255127 GeneCards: AXIN1 Gene
Gene ontology Molecular function • p53 binding • signal transducer activity • GTPase activator activity • protein binding • beta-catenin binding • protein C-terminus binding • enzyme binding • protein kinase binding • receptor signaling complex scaffold activity • ubiquitin protein ligase binding • protein complex scaffold • identical protein binding • protein homodimerization activity • protein self-association • SMAD binding • armadillo repeat domain binding • I-SMAD binding • R-SMAD binding Cellular component • nucleus • cytoplasm • cytosol • cytoplasmic microtubule • plasma membrane • cell cortex • postsynaptic density • cytoplasmic membrane-bounded vesicle • lateral plasma membrane • beta-catenin destruction complex • cytoplasmic vesicle • perinuclear region of cytoplasm • cell periphery Biological process • protein polyubiquitination • in utero embryonic development • optic placode formation • positive regulation of protein phosphorylation • nucleocytoplasmic transport • apoptotic process • activation of JUN kinase activity • determination of left/right symmetry • sensory perception of sound • cell death • dorsal/ventral axis specification • positive regulation of peptidyl-threonine phosphorylation • forebrain anterior/posterior pattern specification • Wnt-activated signaling pathway involved in forebrain neuron fate commitment • cell differentiation • protein catabolic process • negative regulation of Wnt signaling pathway • positive regulation of transforming growth factor beta receptor signaling pathway • olfactory placode formation • cytoplasmic microtubule organization • positive regulation of protein ubiquitination • activation of protein kinase activity • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • positive regulation of peptidyl-serine phosphorylation • negative regulation of transcription elongation from RNA polymerase II promoter • regulation of catenin import into nucleus • post-anal tail morphogenesis • termination of G-protein coupled receptor signaling pathway • positive regulation of GTPase activity • cellular protein complex assembly • negative regulation of fat cell differentiation • positive regulation of protein catabolic process • positive regulation of transcription, DNA-templated • positive regulation of JNK cascade • embryonic eye morphogenesis • axial mesoderm formation • negative regulation of protein metabolic process • protein homooligomerization • positive regulation of ubiquitin-protein transferase activity • muscle cell development • canonical Wnt signaling pathway • embryonic skeletal joint morphogenesis • canonical Wnt signaling pathway involved in neural plate anterior/posterior pattern formation • cellular response to organic cyclic compound • genetic imprinting • negative regulation of canonical Wnt signaling pathway • Wnt signaling pathway involved in somitogenesis • positive regulation of canonical Wnt signaling pathway • positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8312	12005
Ensembl	ENSG00000103126	ENSMUSG00000024182
UniProt	O15169	O35625
RefSeq (mRNA)	NM_003502	NM_001159598
RefSeq (protein)	NP_003493	NP_001153070
Location (UCSC)	Chr 16: 0.29 – 0.35 Mb	Chr 17: 26.14 – 26.2 Mb
PubMed search

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.^[1]

Function

This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin (cadherin-associated protein) beta 1, glycogen synthase kinase 3 beta, protein phosphatase 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. Two transcript variants encoding distinct isoforms have been identified for this gene.^[2]

Structure

The full-length human protein comprises 862 amino acids with a (predicted) molecular mass of 96 kDa. The N-terminal RGS domain, a GSK3 kinase interacting peptide of Axin1 and homologs of the C-terminal DIX domains have been solved at atomic resolution. Large WNT-downregulating central regions have been characterized as intrinsically disordered by biophysical experiments and bioinformatic analysis.^[3] Biophysical destabilization of the folded RGS domain induces formation of nanoaggregates that expose and locally concentrate intrinsically disordered regions, which in turn misregulate Wnt signalling. Many other large IDPs are affected by missense mutations, such as BRCA1, Adenomatous polyposis coli(APC), CREB-binding protein/(CBP) and might be affected in similar ways by missense mutations of their folded domains.^[4]

Interactions

AXIN1 has been shown to interact with:

• APC,^[5]
• CTNNB1,^[5][6]
• CSNK1E,^[7]
• CSNK1A1,^[7]
• DVL1,^[8][9]
• GSK3B,^[5][10]
• LRP5,^[8][11]
• MAP3K1,^[7][12]
• PPP2R5A,^[13] and
• TSC2.^[10]

References

1. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F (August 1997). "The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation". Cell 90 (1): 181–92. doi:10.1016/S0092-8674(00)80324-4. PMID 9230313.
2. "Entrez Gene: AXIN1 axin 1".
3. Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SG, Maurice MM (2011). "Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded" (PDF). J Mol Biol. 405 (3): 773–86. doi:10.1016/j.jmb.2010.11.013. PMID 21087614.
4. Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, Jordens I, Low TY, van Scherpenzeel RC, Kuper I, Richter K, Heck AJ, Boelens R, Vincent JP, Rüdiger SG, Maurice MM. "Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network". Nat Struct Mol Biol. year = 2016. doi:10.1038/nsmb.3191. PMID 26974125.
5. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (June 1998). "Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level". Genes Cells 3 (6): 395–403. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785.
6. Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH (June 2003). "Regulation of the Wnt signaling pathway by disabled-2 (Dab2)". EMBO J. 22 (12): 3084–94. doi:10.1093/emboj/cdg286. PMC 162138. PMID 12805222.
7. Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". J. Biol. Chem. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
8. Kim MJ, Chia IV, Costantini F (November 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB J. 22 (11): 3785–94. doi:10.1096/fj.08-113910. PMC 2574027. PMID 18632848.
9. Li L, Yuan H, Weaver CD, Mao J, Farr GH, Sussman DJ, Jonkers J, Kimelman D, Wu D (August 1999). "Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1". EMBO J. 18 (15): 4233–40. doi:10.1093/emboj/18.15.4233. PMC 1171499. PMID 10428961.
10. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". J. Biol. Chem. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
11. Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (April 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Mol. Cell 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
12. Zhang Y, Neo SY, Han J, Lin SC (August 2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". J. Biol. Chem. 275 (32): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.
13. Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, Van Hoof C, Goris J, Asashima M, Kikuchi A (July 2001). "Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A". J. Biol. Chem. 276 (29): 26875–82. doi:10.1074/jbc.M100443200. PMID 11297546.

Further reading

• Segditsas S, Tomlinson I (2007). "Colorectal cancer and genetic alterations in the Wnt pathway.". Oncogene 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297.
• Flint J, Thomas K, Micklem G, Raynham H, Clark K, Doggett NA, King A, Higgs DR (1997). "The relationship between chromosome structure and function at a human telomeric region". Nat. Genet. 15 (3): 252–7. doi:10.1038/ng0397-252. PMID 9054936.
• Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A (1998). "Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin". EMBO J. 17 (5): 1371–84. doi:10.1093/emboj/17.5.1371. PMC 1170485. PMID 9482734.
• Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998). "Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta". Curr. Biol. 8 (10): 573–81. doi:10.1016/S0960-9822(98)70226-X. PMID 9601641.
• Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (1998). "Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level". Genes Cells 3 (6): 395–403. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785.
• Hsu W, Zeng L, Costantini F (1999). "Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain". J. Biol. Chem. 274 (6): 3439–45. doi:10.1074/jbc.274.6.3439. PMID 9920888.
• Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K, Nakayama K (1999). "An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin". EMBO J. 18 (9): 2401–10. doi:10.1093/emboj/18.9.2401. PMC 1171323. PMID 10228155.
• Fagotto F, Jho Eh, Zeng L, Kurth T, Joos T, Kaufmann C, Costantini F (1999). "Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization". J. Cell Biol. 145 (4): 741–56. doi:10.1083/jcb.145.4.741. PMC 2133179. PMID 10330403.
• Kodama S, Ikeda S, Asahara T, Kishida M, Kikuchi A (1999). "Axin directly interacts with plakoglobin and regulates its stability". J. Biol. Chem. 274 (39): 27682–8. doi:10.1074/jbc.274.39.27682. PMID 10488109.
• Jho Eh, Lomvardas S, Costantini F (2000). "A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression". Biochem. Biophys. Res. Commun. 266 (1): 28–35. doi:10.1006/bbrc.1999.1760. PMID 10581160.
• Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A (2000). "GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin". Oncogene 19 (4): 537–45. doi:10.1038/sj.onc.1203359. PMID 10698523.
• Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y (2000). "AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1". Nat. Genet. 24 (3): 245–50. doi:10.1038/73448. PMID 10700176.
• Spink KE, Polakis P, Weis WI (2000). "Structural basis of the Axin-adenomatous polyposis coli interaction". EMBO J. 19 (10): 2270–9. doi:10.1093/emboj/19.10.2270. PMC 384355. PMID 10811618.
• Zhang Y, Neo SY, Han J, Lin SC (2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". J. Biol. Chem. 275 (32): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.
• Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, Kearney L, Buckle VJ, Doggett NA, Flint J, Higgs DR (2001). "Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16". Hum. Mol. Genet. 10 (4): 339–52. doi:10.1093/hmg/10.4.339. PMID 11157797.
• Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, Van Hoof C, Goris J, Asashima M, Kikuchi A (2001). "Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A". J. Biol. Chem. 276 (29): 26875–82. doi:10.1074/jbc.M100443200. PMID 11297546.
• Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Mol. Cell 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
• Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M (2001). "Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway". Mol. Cell. Biol. 21 (15): 5132–41. doi:10.1128/MCB.21.15.5132-5141.2001. PMC 87238. PMID 11438668.
• Rubinfeld B, Tice DA, Polakis P (2001). "Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon". J. Biol. Chem. 276 (42): 39037–45. doi:10.1074/jbc.M105148200. PMID 11487578.